CN101993404A

CN101993404A - Method for synthesizing N-Boc-3-pyrrolidine formaldehyde

Info

Publication number: CN101993404A
Application number: CN2010105470791A
Authority: CN
Inventors: 刘战朋
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-11-17
Filing date: 2010-11-17
Publication date: 2011-03-30

Abstract

The invention discloses a method for synthesizing N-Boc-3-pyrrolidine formaldehyde, which comprises the following steps of: (1) adding 1mol of glycine and 0.5 to 1.5mol of acrylonitrile into a methylbenzene solvent, refluxing the solution under the action of 1.5 to 2.5mol of paraformaldehyde, cooling and then performing suction filtering on the solution, concentrating the mother solution, distilling the mother solution under reduced pressure, and collecting the fraction of 102 to 105 degrees to obtain 3-cyanopyrrolidine; (2) adding 0.5mol of 3-cyanopyrrolidine obtained in the step (1) into dichloromethane, dripping 0.4 to 0.6mol of Boc acid anhydride into the solution at room temperature under the action of 0.5 to 0.75mol of triethylamine, performing room temperature reaction, washing the reaction solution by using hydrochloric acid solution, and separating, drying and concentrating the solution to obtain N-Boc-3-cyanopyrrolidine; and (3) dissolving 0.4mol of N-Boc-3-cyanopyrrolidine obtained in the step (2) into dichloromethane, cooling the solution, dripping 0.4 to 0.6mol of di-isobutyl aluminum hydride into the solution, dripping hydrochloric acid solution into the reaction solution after reaction to quench the reaction, separating the solution, concentrating the organic phase, distilling the concentrate under reduced pressure, and collecting the fraction of 110 to 114 degrees to obtain the N-Boc-3-pyrrolidine formaldehyde. The synthesizing method has a few steps, high yield and low cost, and is suitable for industrial large-scale production.

Description

A kind of synthetic method of N-Boc-3-tetramethyleneimine formaldehyde

Technical field

The present invention relates to a kind of N-BOC-3-tetramethyleneimine formaldehyde synthetic method, belong to the organism synthesis technical field.

Background technology

N-BOC-3-tetramethyleneimine formaldehyde is the important synthesis material of a lot of medicine, agricultural chemicals and auxiliary, and for example channel receptor agonist, receptor modulators etc. comprise diseases such as treatment pain, central nervous system disease, neuropathy, inflammation.In the last few years, the new drug of a series of N-BOC-3-of containing tetramethyleneimine formaldehyde structures was found, and the demand to this intermediate on the market increases day by day.

By our investigation to market, still do not have any company both at home and abroad and have the ability of producing this compound in batches, existing simultaneously turnout far can not satisfy the demand of world market for this compound.

In the synthetic method of present known N-BOC-3-tetramethyleneimine formaldehyde; it is raw material that patent WO2005049605A1 discloses with N-benzyl-3-pyrrolidinecarboxylic acid ethyl ester, gets the synthetic method of N-BOC-3-tetramethyleneimine formaldehyde through four-step reactions such as shortening debenzylation, BOC protection, sodium borohydride reduction, Swern oxidations.

Synthetic route among the patent WO2005049605A1 is as follows:

Figure 2010105470791100002DEST_PATH_IMAGE001

The benzyl of raw material N-described in this patent-3-pyrrolidinecarboxylic acid ethyl ester market can't be bought, and need oneself to customize and synthesize, be raw material with benzylamine and chloromethyl trimethyl silane, make this raw material through three-step reaction.Route is as follows:

In sum, it is raw material that method in this patent needs with benzylamine and chloromethyl trimethyl silane, reaction just can make N-BOC-3-tetramethyleneimine formaldehyde through seven steps, and middle high-risk such as catalytic hydrogenation, the step very high of comprising to equipment requirements, the reaction step number is many, not easy to operate, cost is high, is difficult to use in to amplify to produce.

Summary of the invention

The technical problem to be solved in the present invention is the defective that overcomes existing synthesis technique, provides that a kind of synthesis step is few, yield is high, is suitable for the synthetic method of suitability for industrialized production.

In order to solve the problems of the technologies described above, the invention provides following technical scheme:

A kind of synthetic method of N-Boc-3-tetramethyleneimine formaldehyde comprises the steps:

(1) 1mol glycine, 0.5-1.5mol vinyl cyanide are added in the solvent toluene, under the effect of 1.5-2.5mol Paraformaldehyde 96, reflux, cooling back suction filtration, mother liquor concentrates, underpressure distillation, collects 102-105 degree cut and gets the 3-Cyanopyrolidine;

(2) step (1) gained 0.5mol 3-Cyanopyrolidine is added in the methylene dichloride, under the effect of 0.5-0.75mol triethylamine, room temperature drips 0.4-0.6molBoc acid anhydrides, room temperature reaction; Use hydrochloric acid soln washing reaction liquid again, separatory, drying, concentrate the N-Boc-3-Cyanopyrolidine;

(3) step (2) gained 0.4mol N-Boc-3-Cyanopyrolidine is dissolved in the methylene dichloride, cooling, drip the 0.4-0.6mol diisobutyl aluminium hydride, the dripping hydrochloric acid solution cancellation reaction of reaction back, separatory concentrates organic phase underpressure distillation, collect 110-114 degree cut, get N-Boc-3-tetramethyleneimine formaldehyde.

Used glycine, vinyl cyanide, toluene, Paraformaldehyde 96, methylene dichloride, triethylamine, methylene dichloride, diisobutyl aluminium hydride etc. are all industrial goods among the present invention, and are cheap and easy to get, greatly reduce cost, and step number is few, the yield height, easy handling is suitable for industrialized mass production.

Description of drawings

Accompanying drawing is used to provide further understanding of the present invention, and constitutes the part of specification sheets, is used from explanation the present invention with embodiments of the invention one, is not construed as limiting the invention.In the accompanying drawings:

Fig. 1 is the nucleus magnetic resonance figure of the inventive method products obtained therefrom.

Embodiment

Below in conjunction with accompanying drawing the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, and be not used in qualification the present invention.

Embodiment 1

(1) 1mol glycine, 1mol vinyl cyanide are added in the solvent 1000ml toluene, under the effect of 2mol Paraformaldehyde 96, refluxed 3 hours, cooling back suction filtration, mother liquor concentrates, the water pump underpressure distillation, collects 102-105 degree cut and gets the 3-Cyanopyrolidine, yield 85%, purity 98%;

(2) step (1) gained 0.5mol3-Cyanopyrolidine is added in the 500ml methylene dichloride, under the effect of 0.55mol triethylamine, room temperature drips 0.5molBoc acid anhydrides, room temperature reaction 12 hours; Use hydrochloric acid soln washing reaction liquid again, separatory, drying, concentrate the N-Boc-3-Cyanopyrolidine, yield 90%, purity 97%;

(3) step (2) gained 0.4mol N-Boc-3-Cyanopyrolidine is dissolved in the 400ml methylene dichloride, be cooled to subzero 20 degree, drip the 0.5mol diisobutyl aluminium hydride, the dripping hydrochloric acid solution cancellation reaction of reaction back, separatory, organic phase is concentrated, 110-114 degree cut is collected in the oil pump underpressure distillation, gets N-Boc-3-tetramethyleneimine formaldehyde, yield 75%, purity 97%.

The nuclear magnetic resonance map of gained N-Boc-3-tetramethyleneimine formaldehyde as shown in Figure 1.

It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.

Claims

1. the synthetic method of a N-Boc-3-tetramethyleneimine formaldehyde is characterized in that:

Method steps is:

Figure 2010105470791100001DEST_PATH_IMAGE001

2. the synthetic method of N-Boc-3-tetramethyleneimine formaldehyde according to claim 1 is characterized in that:

Method steps is:

(1) 1mol glycine, 1mol vinyl cyanide are added in the solvent toluene, under the effect of 2mol Paraformaldehyde 96, reflux, cooling back suction filtration, mother liquor concentrates, underpressure distillation, collects 102-105 degree cut and gets the 3-Cyanopyrolidine;

(2) step (1) gained 0.5mol 3-Cyanopyrolidine is added in the methylene dichloride, under the effect of 0.55mol triethylamine, room temperature drips 0.5molBoc acid anhydrides, room temperature reaction; Use hydrochloric acid soln washing reaction liquid again, separatory, drying, concentrate the N-Boc-3-Cyanopyrolidine;

(3) step (2) gained 0.4mol N-Boc-3-Cyanopyrolidine is dissolved in the methylene dichloride, cooling, drip the 0.5mol diisobutyl aluminium hydride, the dripping hydrochloric acid solution cancellation reaction of reaction back, separatory concentrates organic phase underpressure distillation, collect 110-114 degree cut, get N-Boc-3-tetramethyleneimine formaldehyde.